DEVELOPMENT OF A NEW CLASS OF ULTRASOUND CONTRAST AGENTS

该项目的长期目标是开发和评估新的 用于诊断超声的可注射造影剂。朝向这个方向 目的这项研究将建立在第一次研究中获得的专业知识基础上 授权期，其中表明海藻酸盐的电致凝胶 可用于包裹空气以产生稳定的微泡，这些微泡 在体外和体内都有回声。问题仍然是减少 微泡的直径小于6微摩尔，以便畅通无阻地通过 通过肺床。在藻酸盐研究期间，一种全新的 研制了造影剂。它由表面活性剂稳定的 微泡是通过超声作用于含水混合物而制备的 特殊的表面活性剂。体内外的初步研究 表明该新制剂具有很大的临床应用潜力。一把钥匙 这种新药剂的特点是80%的气泡直径为 小于6微摩尔。 造影剂的开发将在两个方面取得进展。海藻酸盐 系统仍然被认为是有价值的，主要是因为聚合物- 包衣泡泡具有长期稳定性的优点，而且因为钙 海藻酸盐是一种水凝胶，具有高度的柔韧性和变形能力，因此 在对压力的良好抵抗力方面，例如在 心。最近有报道称，使用雾化器来生产 微米级海藻酸盐微胶囊，用作载体 活体疫苗投放。重点将放在适应这一新的 包括在微米大小的胶囊中捕获气体的技术。在……里面 此外，还将研究使用振动板液滴发生器 同样的目的。微米级微气泡的成功生产将 随后进行了广泛的体内和体外表征 与回声(后向散射和衰减)有关的试剂 系数)、稳定性(储存期间和体内注射后) 和生物兼容性。 在进行这些研究的同时，还将继续发展 表面活性剂稳定的微泡。目前的配方一直是 以稳定性、衰减和后向散射为特征 体外系数。计划进行进一步的动物研究，以测试这两种方法 体内稳定性好，强度可作为造影剂。此外，重要的是要 调查正在发生的稳定的机制 表面活性剂/空气在分子水平上的界面。这将使我们能够 定义表面活性剂分子所需的结构性质，以 稳定气泡，这反过来将使我们能够扩大范围 我们可以在这种试剂中使用的分子。此外，它还将 允许选择最大药剂的最佳分子结构 稳定性。涉及朗缪尔槽实验的物理/化学研究 将被用于探测表面活性剂在空气中的分子相互作用- 水界面。 开发一种有效的超声造影剂将是非常有意义的 对医疗保健意义重大。超声波是一种相对便宜、安全的 诊断程序不仅是非侵入性的，而且能产生真实的 人体内部结构的时间图像。

The long term objective of this project is to develop and evaluate new injectable contrast agents for use in diagnostic ultrasound. Towards this aim the research will build upon expertise acquired during the first granting period, where it was shown that ionotropic gelation of alginate can be used to encapsulate air to produce stable microbubbles that are echogenic both in vitro and in vivo. The problem remains to reduce the microbubbles' diameter to below 6 micromoles, to allow unimpeded passage through the pulmonary bed. During the alginate studies an entirely new contrast agent was developed. It consists of surfactant-stabilized microbubbles which are prepared by sonication of aqueous mixtures of particular surfactants. Preliminary studies both in vitro and in vivo indicate that this new agent demonstrates great clinical potential. A key feature of this new agent is that 80% of the bubbles have a diameter of less than 6 micromoles. Contrast agent development will progress along two fronts. The alginate system is still considered to have merit, primarily because a polymer- coated bubble offers advantages of long-term stability and because calcium alginate, being a hydrogel, is highly flexible and deformable, resulting in good resistance to pressures such as those that are encountered in the heart. There have been recent reports of the use of atomizers to produce alginate microcapsules in the micron size range for use as vehicles for in vivo vaccine delivery. Emphasis will be placed on adapting this new technology to include entrapment of a gas in the micron-sized capsules. In addition, the use of a vibrating plate drop generator will be studied for the same purpose. Successful production of micron-sized microbubbles will be followed by extensive in vivo and in vitro characterization of the agent with respect to echogenicity (backscatter and attenuation coefficients), stability (both during storage and after in vivo injection) and biocompatibility. In parallel with these studies, there will be continued development of the surfactant-stabilized microbubbles. The present formulations have been characterized with respect to stability and to attenuation and backscatter coefficients in vitro. Further animal studies are planned to test both in vivo stability, and strength as a contrast agent. Also, it is important to investigate the mechanism of stabilization that is taking place at the surfactant/air interface at the molecular level. This will allow us to define the structural properties required of the surfactant molecule to stabilize air bubbles, which in turn will enable us to broaden the range of molecules available to us for use in this agent. In addition it will allow choice of the optimal molecular structures for maximum agent stability. Physical/chemical studies involving Langmuir trough experiments will be used to probe the molecular interactions of surfactants at air- water interfaces. Development of an effective ultrasound contrast agent would be highly significant to health care. Ultrasound is a relatively inexpensive, safe diagnostic procedure that is not only noninvasive, but also generates real time images of the internal structures of the body.